Levings Application 1 Flashcards
MHC protein numbers (2)
- humans have 6 different genes encoding MHC proteins, with 2 copies of each gene
- total of 12 copies
MHC class I (2)
- 3 MHC class I proteins
- HLA-A, HLA-B, and HLA-C
HLA
- human leukocyte antigen
MHC class II (2)
- 3 MHC class II proteins
- HLA-DP, HLA-DQ, HLA-DR
how are MHC proteins key for diversity (3)
- many different alleles for each MHC gene
- polymorphism maximizes probability of binding to peptides from pathogens
- particular combination of 12 HLAs we each express defines our tissue type
MHC diversity and transplantation
- MHC diversity is why transplanted cells/organs are recognized as non-self
what is the mouse version of the human HLA complex
- mouse H-2 complex
allorecognition
- the ability of an individual organism to distinguish its own tissues from those of another
allorecognition pathways (3)
- direct pathway
- indirect pathway
- semidirect pathway
what percentage of recipient T cells participate in direct pathway allorecognition
- 1-7% of T cells participate in direct recognition for any given donor/host pair depending on degree of donor mismatch
allorecognition: direct pathway
- donor APC presents MHC-donor antigen complex to the TCR of a recipient T cell
allorecognition: direct presentation steps (2)
- donor-derived DCs leave the graft, migrate to LNs, and stimulate naive alloantigen-specific T cells
- activated T cells traffic to graft where they can be restimulated by donor cells expressing MHC and initiate an immune response
which form of presentation is important in early allograft responses
- direct pathway
allorecognition: indirection pathway
- transplanted antigens are processed and presented on recipient MHC from recipient APC to a recipient T cell
allorecognition: semidirect pathway
- transplanted MHC-donor antigen are presented by a recipient APC to a recipient T cells
direct allorecognition types (2)
- peptide centric: donor peptide of donor peptide-MHC is recognized
- MHC centric: MHC peptide of donor peptide-MHC is recognized
transplants vs normal immune response
- capacity of donor-derived cells to participate
- direct recognition of alloantigens
- high freq. of alloAg specific cells in both naive and memory T cell pool
- lifelong presence of Ag
infection in transplantation: 1-12 months after transplant (2)
- maximum immune suppression due to immunosuppressants
- opportunistic infections, relapses, and reactivations
infection in transplantation: over 12 months (2)
- late-onset infections
- opportunistic infections and community-acquired infections
clinical application of strategies to induce tolerance (2)
- central tolerance strategies (deletion)
- peripheral tolerance strategies (anergy & suppression)
clinical application of strategies to induce tolerance: central tolerance
- HSC transplantation to re-set central tolerance
clinical application of strategies to induce tolerance: peripheral tolerance (2)
- co-stimulation blockade/modulation
- cell therapy with regulatory immune cells
- in vivo boosting of regulatory immune cells
HSC transplantation: autologous transplantation
- benefit
- risks (2)
- benefit: no risk of graft versus host disease
- risk: incomplete ablation of autoreactive cells
- risk: same genetic risk factors in immune cells
HSC transplantation: allogeneic transplantation
- benefits (2)
- risk
- benefit: reduced genetic risk of autoimmunity
- benefit: assuming complete reconstitution, no space for autoreactive cells
- risk: graft versus host disease
allogeneic
- individuals of the same species who are genetically different and immunologically incompatible
autologous
- cell/tissues obtained from same individual
graft versus host disease
- T cells of the donated stem cells/bone marrow cells attack the host cells
Tregs as cellular therapy to induce transplantation tolerance: Treg sources (2)
- can be taken from patient
- can be from third source (blood donation, cord blood, thymus, etc)
Tregs as cellular therapy to induce transplantation tolerance (3)
- Tregs taken from sources and undergo in vitro expansion
- cell therapy to insert Tregs back into patient
- Tregs police immune system, regulate and control immune responses to stop graft rejection and graft vs host disease
Treg cell therapies examples (7)
- type 1 & 2 diabetes
- MS
- rhematoid arthritis
- IBD
- allergies
- allograft rejection
- graft versus host disease
strategies to block Tregs applications (3)
- cancer
- chronic infections
- vaccination
regulatory cell therapy paper: kidney rejection outcomes
- CTG had slightly lower rate of biopsy confirmed acute rejection compared to RGT
regulatory cell therapy paper: infection outcomes
- CTG had lower rate of infection compared to RGT
regulatory cell therapy paper: effects on immune cell populations
- RGT patients had major alterations in absolute and relative blood immune cell population composition compared with healthy controls
regulatory cell therapy paper: effects on Tregs
- no significant difference in number/proportions of Tregs between groups 60 weeks post-kidney transplant
resetting central tolerance: HSCT for solid organ transplant steps (7)
- conditioning drug regime
- transplantation of donor BM
- donor HSC engraftment
- multilineage chimerism
- peripheral tolerance (intragraft)
- peripheral tolerance (secondary lymphoid organs)
- central tolerance
re-setting central tolerance: HSCT for solid organ transplant; thymus (4)
- recipient and donor bone marrow enter thymus
- alloreactive T cell from both donor and recipient in thymus
- alloreactive recipient and donor T cells negatively selected and die
- mature, non-alloreactive T cells escape to blood as a mixed chimera
